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2.
Ann Rheum Dis ; 79(1): 132-140, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31662318

RESUMO

OBJECTIVES: Diverse evidence including clinical, genetic and microbiome studies support a major role of the gut microbiome in the common immune-mediated arthropathy, ankylosing spondylitis (AS). We set out to (1) further define the key microbial characteristics driving disease, and (2) examine the effects of tumour necrosis factor-inhibitor (TNFi) therapy upon the microbiome. METHODS: The stools from a case-control cohort of 250 Han-Chinese subjects underwent shotgun metagenomic sequencing. All subjects were genotyped using the Illumina CoreExome SNP microarray. RESULTS: Previous reports of gut dysbiosis in AS were reconfirmed and several notable bacterial species and functional categories were differentially abundant. TNFi therapy was correlated with a restoration the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. Enrichment of bacterial peptides homologous to HLA-B27-presented epitopes was observed in the stools of patients with AS, suggesting that either HLA-B27 fails to clear these or that they are involved in driving HLA-B27-associated immune reactions. TNFi therapy largely restored the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. TNFi therapy of patients with AS was also associated with a reduction of potentially arthritogenic bacterial peptides, relative to untreated patients. CONCLUSION: These findings emphasise the key role that the gut microbiome plays in driving the pathogenesis of AS and highlight potential therapeutic and/or preventative targets.

3.
Front Med (Lausanne) ; 6: 271, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824954

RESUMO

Background: Ankylosing spondylitis (AS) is a rheumatic inflammatory disease with unknown etiology, and fatigue is one of the main systemic symptoms of AS. The aim of the current study was to explore the mechanism of AS-associated fatigue (ASF) from multiple aspects, including neuropsychological changes. Method: A total of 120 AS patients and 78 age- and sex-matched healthy individuals were recruited into the study. Fatigue was assessed by the fatigue item of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Multidimensional Assessment of Fatigue (MAF) scale. Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS). The cortical thickness and subcortical gray matter volume were assessed using a Philips Achieva 3.0 T TX MRI scanner. Result: Of the 120 AS patients, 103 (85.8%) reported varying degrees of fatigue. Among these fatigue cases, 33 (32.0%) were in the severe fatigue group (BASDAI-Fatigue ≥ 5), and 70 patients (68.0%) were considered to be in the mild fatigue group (BASDAI-Fatigue > 0 but <5). The BASDAI, ASDAS-CRP, HAD-A, and HAD-D scores of AS patients in the severe fatigue group were all significantly higher than those of patients in the mild fatigue and non-fatigue groups (all, P < 0.05). The structural equation model suggested that AS activity triggered the occurrence of fatigue by inducing psychological change. Finally, head MRI imaging found that the left thalamus volume in AS patients with severe fatigue was significantly larger than that in non-fatigue AS patients and healthy controls (both, P < 0.05). Conclusion: The study revealed neuropsychological factors involved in fatigue in AS.

4.
Proc Natl Acad Sci U S A ; 116(37): 18550-18560, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31451659

RESUMO

Excessive self-reactive and inadequate affinity-matured antigen-specific antibody responses have been reported to coexist in lupus, with elusive cellular and molecular mechanisms. Here, we report that the antigen-specific germinal center (GC) response-a process critical for antibody affinity maturation-is compromised in murine lupus models. Importantly, this defect can be triggered by excessive autoimmunity-relevant CD11c+Tbet+ age-associated B cells (ABCs). In B cell-intrinsic Ship-deficient (ShipΔB) lupus mice, excessive CD11c+Tbet+ ABCs induce deregulated follicular T-helper (TFH) cell differentiation through their potent antigen-presenting function and consequently compromise affinity-based GC selection. Excessive CD11c+Tbet+ ABCs and deregulated TFH cell are also present in other lupus models and patients. Further, over-activated Toll-like receptor signaling in Ship-deficient B cells is critical for CD11c+Tbet+ ABC differentiation, and blocking CD11c+Tbet+ ABC differentiation in ShipΔB mice by ablating MyD88 normalizes TFH cell differentiation and rescues antigen-specific GC responses, as well as prevents autoantibody production. Our study suggests that excessive CD11c+Tbet+ ABCs not only contribute significantly to autoantibody production but also compromise antigen-specific GC B-cell responses and antibody-affinity maturation, providing a cellular link between the coexisting autoantibodies and inadequate affinity-matured antigen-specific antibodies in lupus models and a potential target for treating lupus.

5.
Front Immunol ; 10: 887, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31105703

RESUMO

TNFα inhibitors have shaped the landscape of rheumatoid arthritis (RA) therapy with high clinical efficiency. However, their impact on T cell recall responses is not well-elucidated. We aimed to analyze the immune profiles of memory T cells in RA patients undergoing TNFα inhibitor Golimumab (GM) treatment. Frequencies of peripheral T cell subsets and cytokine expression profiles in memory T cells (TM) upon PMA/Ionomycine stimulation were determined by flow cytometry. Antigen-specific CD8 T cell immunity was analyzed through stimulating PBMCs with CMV-EBV-Flu (CEF) viral peptide pool and subsequent intracellular IFNγ staining. Both peripheral CD8 and CD4 T cells from GM treated patients had a shift pattern characterized by an enlarged effector TM and a reduced central TM cell population when compared to GM untreated group. An increase in the frequencies of TNFα+, IL-2+, and IL-17+ CD8 TM cells was observed whereas only TNFα+CD4 TM cells increased in GM treated patients. Moreover, GM treated patients contained more peripheral IFNγ-producing CD8 T cells specific to CEF viral peptides. Together, these results show a distinct T cell subset pattern and enhanced memory T cell immunity upon GM treatment, suggesting an immunoregulatory effect of TNF inhibitor Golimumab on peripheral memory T cell responses.

6.
Endocrine ; 64(3): 648-656, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30887277

RESUMO

PURPOSE: Hyperprolactinemia (HPRL) has been reported in many autoimmune diseases. However, the serum autoantibody profile and peripheral B-cell subset distribution in women with HPRL are largely unknown. The current study aimed to investigate the autoantibody prevalence and cytokine levels as well as to further explore the B-cell subset distribution in women with HPRL. METHODS: Sera from 202 women with HPRL and 97 healthy women were included in this study. All sera were examined for prolactin (PRL), anti-nuclear antibody (ANA), rheumatoid factor, anticardiolipin (ACL), immunoglobulin G, immunoglobulin M, complement 3, complement 4, interleukin 4 (IL-4) and interleukin 6 (IL-6). Peripheral blood was collected from 22 women with HPRL and 19 healthy women, and B-cell subsets were measured by flow cytometry. RESULTS: At least one autoantibody was found in 47 out of 202 women with HPRL compared with 9 of 97 healthy women (p < 0.001). The levels of IL-4 (p < 0.0001) and IL-6 (p < 0.0001) were significantly higher in women with HPRL than in healthy women. The percentages of naive IgD+IgM- B cells (BND cells, p < 0.0001), antibody-secreting cells (p = 0.007) and unswitched memory B cells (p = 0.004) among the total B cells from HPRL women were significantly higher than those from healthy women. CONCLUSIONS: Women with HPRL had a higher prevalence of autoantibodies, higher serum levels of IL-4 and IL-6, and more BND cells, antibody-secreting B cells and unswitched memory B cells than healthy women. These data imply that a high level of PRL is associated with autoimmune diseases.

7.
Front Med ; 13(4): 411-419, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30635780

RESUMO

Although many drugs and therapeutic strategies have been developed for rheumatoid arthritis (RA) treatment, numerous patients with RA fail to respond to currently available agents. In this review, we provide an overview of the complexity of this autoimmune disease by showing the rapidly increasing number of genes associated with RA.We then systematically review various factors that have a predictive value (predictors) for the response to different drugs in RA treatment, especially recent advances. These predictors include but are certainly not limited to genetic variations, clinical factors, and demographic factors. However, no clinical application is currently available. This review also describes the challenges in treating patients with RA and the need for personalized medicine. At the end of this review, we discuss possible strategies to enhance the prediction of drug responsiveness in patients with RA.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Biomarcadores , Medicina de Precisão , Resistência a Medicamentos , Expressão Gênica , Genótipo , Humanos , Fator de Necrose Tumoral alfa/genética
8.
Clin Exp Rheumatol ; 37(2): 227-234, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30183595

RESUMO

OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) in combination with methotrexate (MTX) in Chinese patients with active rheumatoid arthritis (RA) and an inadequate response to MTX. METHODS: This 24-week, phase 3, double-blind, placebo-controlled study was conducted in 30 centres across China. A total of 430 patients were randomised 3:1 to receive CZP 200 mg every 2 weeks (loading dose: 400 mg CZP at Weeks 0, 2 and 4) plus MTX or placebo (PBO) plus MTX. The primary endpoint was ACR20 response at Week 24, for which the superiority of CZP+MTX over PBO+MTX was evaluated. Additional parameters for clinical efficacy, health outcomes, immunogenicity and safety were assessed. RESULTS: At Week 24, 54.8% of CZP+MTX patients and 23.9% of PBO+MTX patients achieved ACR20 (odds ratio: 3.9, p<0.001). CZP+MTX patients also achieved greater improvements in HAQ-DI, higher ACR50/70 responses and higher DAS28(ESR) remission rate at Week 24. Rapid onset of response to CZP+MTX was observed as early as Week 1 for most of the clinical, functional and patient-reported outcomes. Incidences of treatment-emergent adverse events (TEAEs) were similar between treatment arms. Serious TEAEs were reported by 6.3% of CZP+MTX patients and 2.7% of PBO+MTX patients. No new safety signals were observed. CONCLUSIONS: CZP in combination with MTX showed an acceptable safety profile, a rapid onset of response and sustained effects in reducing the signs and symptoms of RA and improving physical function in Chinese patients with RA and an inadequate response to MTX.


Assuntos
Antirreumáticos , Artrite Reumatoide , Certolizumab Pegol/uso terapêutico , Metotrexato/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , China , Método Duplo-Cego , Quimioterapia Combinada , Humanos , Indução de Remissão , Resultado do Tratamento
9.
Chin Med J (Engl) ; 131(22): 2683-2692, 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30425195

RESUMO

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This study assessed the efficacy and safety of tofacitinib in Chinese patients with RA enrolled in Phase 3 and long-term extension (LTE) studies. Methods: ORAL Sync was a 1-year, randomized, placebo-controlled, Phase 3 trial. Patients received tofacitinib 5 or 10 mg twice daily (BID) or placebo advanced to tofacitinib 5 or 10 mg BID at 3 or 6 months. All patients remained on ≥1 background conventional synthetic disease-modifying antirheumatic drug. ORAL Sequel is an open-label LTE study (data-cut: March 2015; data collection and analyses were ongoing, and study database was not locked at the time of analysis; study was closed in 2017). Efficacy outcomes: American College of Rheumatology (ACR) 20/50/70 response rates and Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-4 [ESR]). Patient- and physician-reported outcomes: Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient and Physician Global Assessment of Arthritis, and pain (visual analog scale). Safety was assessed throughout. Results: ORAL Sync included 218 patients; 192 were subsequently enrolled into ORAL Sequel. In ORAL Sync, more patients achieved ACR20 (tofacitinib 5 mg BID, 67.4%; 10 mg BID, 70.6%; placebo, 34.1%) and DAS28-4 (ESR) <2.6 (tofacitinib 5 mg BID, 7.1%; 10 mg BID, 13.1%; placebo, 2.3%) with tofacitinib versus placebo at Month 6. Mean changes from baseline in HAQ-DI were greater with tofacitinib versus placebo at Month 6. In ORAL Sequel, efficacy was consistent to Month 48. Incidence rates for adverse events of special interest in tofacitinib-treated patients were similar to the global population. Conclusions: Tofacitinib significantly reduced signs/symptoms and improved physical function and quality of life in Chinese patients with moderate-to-severely active RA up to Month 48. The safety profile was consistent with the global population. Clinical Trial Identifier: NCT00856544 and NCT00413699.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Administração Oral , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto Jovem
10.
Front Immunol ; 9: 2641, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30487798

RESUMO

Objective: Despite extensive studies, the precise mechanism underlying spondyloarthritis, especially ankylosing spondylitis, remains elusive. This study aimed to develop an ideal animal model for an insight into mechanism of spondyloarthritis and functional relevance of SOCS3 in spondyloarthritis. Methods: Since SOCS3 is a major regulator of IL23-STAT3 signaling, we generated SOCS3 knockdown transgenic (TG) mice for development of an animal model of spondyloarthritis. A hydrodynamic delivery method was employed to deliver minicircle DNA expressing IL23 (mc-IL23) into wild-type (WT) and the TG mice. Knockdown/overexpression systems mediated by lentivirus and retrovirus were used to determine whether SOCS3 regulated osteoblast differentiation. Results: Forced expression of IL23 induced severe joint destruction and extensive bone loss in SOCS3 knockdown TG mice, while this treatment only caused moderate symptoms in WT mice. Furthermore, severe spondyloarthritis was found in IL23-injected TG mice as compared to mild disease observed in WT controls under same condition. Moreover, our studies showed that IL23 promoted osteoblast differentiation via activation of STAT3 pathway and disruption of SOCS3 expression greatly increased phosphorylation of STAT3. In addition, silencing SOCS3 resulted in enhanced osteoblast differentiation through activation of Smad1/5/9 signaling, as evidenced by elevated phosphorylation level of Smad1/5/9. Experiments further demonstrated that SOCS3 interacted with Smad1 and thus suppressed the BMP2-Smad signaling. Conclusions: The results reveal that SOCS3 is involved in IL23-induced spondyloarthritis and acts as a key regulator of osteoblast differentiation, and suggest that SOCS3 knockdown TG mice may be an ideal animal model for further studies of spondyloarthritis.


Assuntos
Diferenciação Celular , Interleucina-23 , Osteoblastos , Transdução de Sinais , Proteína 3 Supressora da Sinalização de Citocinas , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Linhagem Celular , DNA Circular/efeitos adversos , DNA Circular/genética , DNA Circular/imunologia , DNA Circular/farmacologia , Modelos Animais de Doenças , Inativação Gênica , Interleucina-23/efeitos adversos , Interleucina-23/genética , Interleucina-23/imunologia , Camundongos , Camundongos Knockout , Osteoblastos/imunologia , Osteoblastos/patologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Espondilite Anquilosante/induzido quimicamente , Espondilite Anquilosante/genética , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/patologia , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/imunologia
12.
Chin Med J (Engl) ; 131(2): 171-179, 2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29336365

RESUMO

BACKGROUND: Interleukin (IL)-37, also called IL1F7, is a natural inhibitor of inflammatory and immune responses. It is involved in the pathogenesis of rheumatoid arthritis (RA). This study aimed to investigate the role of IL1F7 gene polymorphism in RA susceptibility in a large cohort of patients. METHODS: Five selected single-nucleotide polymorphisms in IL1F7 genes (rs2723186, rs3811046, rs4241122, rs4364030, and rs4392270) were genotyped by TaqMan Allelic Discrimination in Northern Chinese Han population. The allele and the genotype were compared between patients with RA and healthy controls. Association analyses were performed on the entire data set and on different RA subsets based on the status of the anti-cyclic citrullinated peptide antibody and the rheumatoid factor by logistic regression, adjusting for age and gender. RESULTS: Trend associations were detected between rs2723186, rs4241122, rs4392270, and RA in Stage I (160 patients with RA; 252 healthy controls). Further validation in Stage II comprised 730 unrelated patients with RA (mean age: 54.9 ± 12.6 years; 81.6% females) and 778 unrelated healthy individuals (mean age: 53.5 ± 15.7 years; 79.5% females). No significant differences in the distributions of alleles and genotypes were observed between the case and control groups in both the entire set and the different RA subsets. Disease activity and age of RA onset were also not associated with genotype distributions. CONCLUSION: IL1F7 gene polymorphism does not significantly influence RA susceptibility in the Northern Chinese Han population.


Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença , Interleucina-1/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/etnologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
13.
Arthritis Rheumatol ; 70(2): 287-297, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29044928

RESUMO

OBJECTIVE: Recent evidence from genetic, cell biology, and animal model studies has suggested a pivotal role of autophagy in mediating systemic lupus erythematosus (SLE). However, the genetic basis has not yet been thoroughly examined. Therefore, the aim of the present study was to identify additional susceptibility variants in autophagy-related genes along with their functional significance. METHODS: First, we performed a gene family-based genetic association analysis in SLE patients with the use of ImmunoChip arrays, and then we selected the most strongly associated polymorphisms for replication in additional cohorts. To identify regulatory clues, we analyzed publicly available blood expression quantitative trait locus data and Encyclopedia of DNA Elements data on transcription factor binding sites and cell type-specific differential expression. Functional effects were tested by luciferase reporter assays, electrophoretic mobility shift assays, and differential gene expression assays. RESULTS: In 14,474 samples, we observed that the rare Chinese variant rs933717T was associated with susceptibility to SLE (0.11% in cases versus 0.87% in controls; P = 2.36 × 10-10 , odds ratio 0.13). The rs933717 risk allele C correlated with increased MAP1LC3B expression; increased MAP1LC3B messenger RNA was observed in SLE patients and in lupus-prone mice. In reporter gene constructs, the risk allele increased luciferase activity up to 2.7-3.8-fold in both HEK 293T and Jurkat cell lines, and the binding of HEK 293T and Jurkat cell nuclear extracts to the risk allele was also increased. CONCLUSION: We observed a likely genetic association between light chain 3B, a widely used marker for autophagy, and susceptibility to SLE.


Assuntos
Proteínas F-Box/genética , Lúpus Eritematoso Sistêmico/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Supressoras de Tumor/genética , Adulto , Alelos , Animais , Grupo com Ancestrais do Continente Asiático/genética , Autofagia/genética , Western Blotting/métodos , Linhagem Celular , Biologia Computacional , Ensaio de Desvio de Mobilidade Eletroforética/métodos , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
14.
Arthritis Res Ther ; 19(1): 250, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-29141665

RESUMO

BACKGROUND: This study aimed to investigate the reliability and validity of serum matrix metalloproteinase-3 (MMP-3) levels and articular ultrasound (US) scores in assessing disease activity and therapeutic response in rheumatoid arthritis (RA) patients. METHODS: A total of 151 RA patients were enrolled, of whom 22 were treated with certolizumab pegol (Cimzia, CZP). The RA patients were divided into the following four subgroups according to their disease activity score in 28 joints (DAS28): stable, mild activity, moderate activity, and high activity. Forty-three healthy controls were simultaneously studied. The serum MMP-3 levels and 7-joint US (US7) scores of all subjects were determined. The patients who were treated with CZP were subsequently followed for 6 months. RESULTS: The serum MMP-3 levels of all the RA patients were significantly higher than those of healthy controls, and those of patients with moderate and severe RA were significantly higher than those of patients with stable RA. The US7 scores of patients with severe RA were significantly higher than those of patients in other groups. Using the DAS28 as a reference standard, the corresponding cutoff value of MMP-3 was 70.5 ng/ml. After CZP treatment, the MMP-3 levels and US7 scores were significantly decreased at week 2, and the mean changes in US7 scores at weeks 12 and 24 were significantly higher in both groups with American College of Rheumatology 50% positive response (ACR50) and ACR 70% positive response (ACR70) than in the negative groups. CONCLUSION: Serum MMP-3 and the US7 scores could both effectively reflect disease activity and therapeutic responses in patients with moderate to severe RA. TRIAL REGISTRATION: CTR20140405 (RA0044), CTR20140405: A phase 3, Multicenter, Double-blind, Placebo Controlled, Parallel Group, Randomized, 24-Week Study to Evaluate the Safety and Efficacy of Certolizumab Pegol as Additional Medication to Methotrexate in Chinese Subjects With Active Rheumatoid Arthritis Who Have an Incomplete Response to Methotrexate, Registered on 13 June 2014. CTR20140412 (RA0078), CTR20140412: A phase 3, Multicenter, Open-label Extension Study to Assess the Safety and Efficacy of Certolizumab Pegol as Additional Medication to Methotrexate in Chinese Subjects With Active Rheumatoid Arthritis Who Participated in RA0044, Registered on 02 July 2014.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Certolizumab Pegol/uso terapêutico , Articulações/diagnóstico por imagem , Metaloproteinase 3 da Matriz/sangue , Ultrassonografia/métodos , Adulto , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico por imagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
15.
Genome Med ; 9(1): 97, 2017 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-29149916

RESUMO

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterised by the degeneration of motor neurons, which are responsible for voluntary movement. There remains limited understanding of disease aetiology, with median survival of ALS of three years and no effective treatment. Identifying genes that contribute to ALS susceptibility is an important step towards understanding aetiology. The vast majority of published human genetic studies, including for ALS, have used samples of European ancestry. The importance of trans-ethnic studies in human genetic studies is widely recognised, yet a dearth of studies of non-European ancestries remains. Here, we report analyses of novel whole-exome sequencing (WES) data from Chinese ALS and control individuals. METHODS: WES data were generated for 610 ALS cases and 460 controls drawn from Chinese populations. We assessed evidence for an excess of rare damaging mutations at the gene level and the gene set level, considering only singleton variants filtered to have allele frequency less than 5 × 10-5 in reference databases. To meta-analyse our results with a published study of European ancestry, we used a Cochran-Mantel-Haenszel test to compare gene-level variant counts in cases vs controls. RESULTS: No gene passed the genome-wide significance threshold with ALS in Chinese samples alone. Combining rare variant counts in Chinese with those from the largest WES study of European ancestry resulted in three genes surpassing genome-wide significance: TBK1 (p = 8.3 × 10-12), SOD1 (p = 8.9 × 10-9) and NEK1 (p = 1.1 × 10-9). In the Chinese data alone, SOD1 and NEK1 were nominally significantly associated with ALS (p = 0.04 and p = 7 × 10-3, respectively) and the case/control frequencies of rare coding variants in these genes were similar in Chinese and Europeans (SOD1: 1.5%/0.2% vs 0.9%/0.1%, NEK1 1.8%/0.4% vs 1.9%/0.8%). This was also true for TBK1 (1.2%/0.2% vs 1.4%/0.4%), but the association with ALS in Chinese was not significant (p = 0.14). CONCLUSIONS: While SOD1 is already recognised as an ALS-associated gene in Chinese, we provide novel evidence for association of NEK1 with ALS in Chinese, reporting variants in these genes not previously found in Europeans.


Assuntos
Esclerose Amiotrófica Lateral/genética , Quinase 1 Relacionada a NIMA/genética , Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Humanos , Risco , Sequenciamento Completo do Exoma
16.
Front Med (Lausanne) ; 4: 76, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28674691

RESUMO

OBJECTIVES: Cigarette smoking has been shown in European populations to be associated with rheumatoid arthritis (RA) susceptibility. This study aims to examine the association of smoking with RA in the Han Chinese population. METHODS: 718 Han Chinese RA patients and 404 healthy controls were studied. The associations of cigarette smoking (current, former or ever vs. never smokers, and pack-years of exposure) with RA, anti-cyclic citrullinated peptide antibody (ACPA) positive RA, IgM rheumatoid factor (RF) positive RA, and baseline radiographic erosions (modified van der Heijde-Sharp scores) were assessed. The interaction between smoking and the HLA-DRB1 shared epitope (SE) in RA was also examined. RESULTS: In this study, 11 (1.53%) cases and 6 (1.49%) controls were former smokers (p = 0.95), while 95 (13.23%) cases and 48 (11.88%) controls were current smokers (p = 0.52). Trends toward associations between smoking status (ever vs. never) with RA-overall (p = 0.15, OR = 1.44), ACPA-positive RA (p = 0.24, OR = 1.37), RF-positive RA (p = 0.14, OR = 1.46), or the presence of radiographic erosions (p = 0.66, OR = 1.28) were observed although individually here were not statistically significant. There was no evidence of statistical interaction between smoking status (ever vs. never) and SE for all RA, ACPA-positive RA, ACPA-negative RA, RF-positive RA, RF-negative RA (p = 0.37, 0.50, 0.24, 0.26, and 0.81 respectively), and the 95% CI for the attributable proportion for all interactions included 0. CONCLUSION: This is the first study to examine the association of cigarette smoking with RA in the Han Chinese population. This study shows a trend toward an interaction between smoking and SE carriage influencing the risk of RA, though findings were not statistically significant. It is possible that in the presence of universal exposure to heavy air pollution the effect of smoking on RA risk may be obscured.

17.
J Int Med Res ; 45(6): 2153-2157, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28643532

RESUMO

Renal infarction is a rare clinical entity that is not easily detected by low-sensitivity ultrasound. We herein report a case of dermatomyositis with renal infarction detected during corticosteroid therapy. The patient was followed up for 18 months. A woman who was clinically diagnosed with dermatomyositis complained of severe pain in the right flank of the low back and abdomen, accompanied by nausea and vomiting during corticosteroid therapy. Based on the findings of routine blood tests, abdominal X-ray radiography, and abdominal ultrasound, the patient was diagnosed with acute gastroenteritis and treated with levofloxacin. However, her symptoms were not relieved. Abdominal contrast-enhanced computed tomography revealed renal infarction. Clinicians should be alert to the occurrence of thrombosis, especially when it manifests as vasculitis in patients with rheumatic disease who complain of severe abdominal pain, because it may suggest the presence of renal infarction.


Assuntos
Dermatomiosite/complicações , Nefropatias/complicações , Dermatomiosite/diagnóstico por imagem , Feminino , Humanos , Nefropatias/diagnóstico por imagem , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X
18.
Medicine (Baltimore) ; 96(22): e6737, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28562527

RESUMO

RATIONALE: Systemic Scleroderma (SSc) is a rare connective tissue disease clinically characterized by cutaneous sclerosis and variable systemic involvement. No drug is currently available to effectively reverse the fibrotic process in SSc. Previous reports have suggested that the tumor necrosis factor (TNF) antagonists could be useful for the treatment of fibrotic disorders. However, TNFα has long been considered as an antifibrotic cytokine. Whether TNF antagonist is effective for SSc patients needs to be tested. PATIENT CONCERNS-DIAGNOSIS: Here we report a case with a 2-year history of SSc who was effectively treated with infliximab in our clinic. INTERVENTIONS: The patient manifested skin thickening, chest tightness and arthralgia. Before admitted to our clinic, he was treated with methylprednisolone, prostacyclin, D-penicillamine and calcium antagonists but without significant improvement of his signs and symptoms. In our clinic, the patient was treated with infliximab. OUTCOMES: His signs and symptoms were continued improving during the course of treatment. His skin biopsy showed significant reduction in fibroplasia finally. LESSONS: TNF antagonist is an effective treatment for SSc.


Assuntos
Fármacos Dermatológicos/uso terapêutico , Infliximab/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Idoso , Humanos , Masculino , Escleroderma Sistêmico/patologia , Pele/efeitos dos fármacos , Pele/patologia
19.
Am J Hum Genet ; 99(2): 366-74, 2016 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-27486778

RESUMO

Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n = 7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p = 1.4 × 10(-9)), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1, explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping.


Assuntos
Artrite Reumatoide/genética , Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Antígenos HLA-D/genética , Autoanticorpos , Citrulina , Grupos Étnicos/genética , Europa (Continente)/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Cadeias HLA-DRB1/genética , Humanos , Japão/etnologia , Desequilíbrio de Ligação/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
20.
Microbiol Immunol ; 60(7): 497-500, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27301339

RESUMO

In this study, the mucosal adjuvant activity of Salmonella flagellin as a carrier in a conjugate of EXP153-rFliC was investigated. EXP153-rFliC was made by conjugation of a synthetic B-cell epitope peptide derived from Plasmodium falciparum exported protein-1(EXP153) to recombinant phase 1 flagellin of Salmonella enterica serovar Typhimurium expressed in Escherichia coli (rFliC), and used to immunize BALB/c mice via intranasal instillation. It was found that robust EXP153-specific serum IgG antibodies were induced without additional adjuvant. EXP153-specific sIgA antibodies were also induced, these being detected in bronchoalveolar, nasal, vaginal and intestinal washes. These observations demonstrate that Salmonella flagellin as a carrier is an effective mucosal adjuvant in that its conjugated peptide induces antibody responses.


Assuntos
Anticorpos Antibacterianos/imunologia , Formação de Anticorpos/imunologia , Flagelina/imunologia , Imunidade nas Mucosas , Mucosa Nasal/imunologia , Fragmentos de Peptídeos/imunologia , Salmonella typhimurium/imunologia , Administração Intranasal , Animais , Especificidade de Anticorpos/imunologia , Feminino , Flagelina/química , Imunoglobulina A Secretora/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Camundongos , Fragmentos de Peptídeos/administração & dosagem
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